区域淋巴结转移是结直肠癌患者生存结果的重要预测因素和术后辅助化疗的指标。即使辅助化疗方案取得进展，5年远处转移和生存率仍然不能令人满意。在这里，我们评估了 II-III 期结肠癌 (COAD) 患者中 HMGB1 受体多态性的临床意义，HMGB1 是化疗诱导的免疫原性细胞死亡的标志。我们发现接受辅助化疗的 III 期 COAD 患者会产生高胞质 HMGB1。具有TLR1-N248S多态性（rs4833095）的患者会导致HMGB1介导的TLR1-TLR2信号传导功能丧失，可能会影响辅助化疗的疗效，导致5年内发生远处转移的高风险[HR = 1.694，95% CI = 1.063-2.698，p = 0.027]，提示TLR1-N248S是局部晚期结肠癌患者的独立预后因素。我们发现，在免疫原性化疗奥沙利铂 (OXP) 治疗下，在树突状细胞 (DC) 成熟过程中，TLR1 缺陷会损害 TLR1/2 信号传导，从而产生抗肿瘤免疫反应。 DC上有缺陷的TLR1损害了HMGB1的成熟能力，并减少了T细胞分泌IFNγ以在体外消灭肿瘤细胞。此外，通过 OXP 治疗，TLR1/2 的全身抑制显着减少了肿瘤浸润免疫细胞，导致 OXP 的治疗反应较差。相比之下，TLR1/2激动剂的施用可协同增加OXP治疗的益处并引发高密度的肿瘤浸润免疫细胞。我们还观察到，在携带 TLR1-N248S 多态性的患者的肿瘤微环境中，肿瘤浸润性细胞毒性 T 淋巴细胞较少。总体而言，我们的结果表明，功能失调的 TLR1 可能会通过损害 HMGB1 介导的 DC 成熟并减弱局部晚期结肠癌患者的抗肿瘤免疫反应来降低对辅助化疗的治疗反应。© 2023。作者。

Regional lymph node metastasis is an important predictor for survival outcome and an indicator for postoperative adjuvant chemotherapy in patients with colorectal cancer. Even with advances in adjuvant chemotherapeutic regimens, 5-year distant metastasis and survival rates are still unsatisfactory. Here, we evaluate the clinical significance of polymorphisms in receptors for HMGB1, which is the hallmark of chemotherapy-induced immunogenic cell death, in patients with stage II-III colon carcinoma (COAD). We found that high cytosolic HMGB1 is elicited in stage III COAD patients who received adjuvant chemotherapy. Patients with the TLR1-N248S polymorphism (rs4833095), which causes loss-of-function in HMGB1-mediated TLR1-TLR2 signaling, may influence the therapeutic efficacy of adjuvant chemotherapy, leading to a high risk of distant metastasis within 5 years [HR = 1.694, 95% CI = 1.063-2.698, p = 0.027], suggesting that TLR1-N248S is an independent prognostic factor for locally advanced colon carcinoma patients. We found that defective TLR1 impaired TLR1/2 signaling during dendritic cell (DC) maturation for the antitumor immune response under immunogenic chemotherapy oxaliplatin (OXP) treatment. Defective TLR1 on DCs impaired their maturation ability by HMGB1 and reduced the secretion of IFNγ from T cells to eradicate tumor cells in vitro. Moreover, systemic inhibition of TLR1/2 dramatically reduced the tumor-infiltrating immune cells by OXP treatment, leading to poor therapeutic response to OXP. In contrast, administration of a TLR1/2 agonist synergistically increased the benefit of OXP treatment and triggered a high density of tumor-infiltrating immune cells. We also observed that fewer tumor-infiltrating cytotoxic T lymphocytes were located within the tumor microenvironment in patients bearing the TLR1-N248S polymorphism. Overall, our results suggest that dysfunctional TLR1 may reduce the therapeutic response to adjuvant chemotherapy by impairing HMGB1-mediated DC maturation and attenuating the antitumor immune response in locally advanced colon carcinoma patients.© 2023. The Author(s).